A key function of Lactoferrin is the ability to regulate iron in the body.  It belongs to the group of transferrins, and can pick up & distribute tri-valent iron.  In this way, it can offer a therapeutic approach to problems with iron metabolism. (See also Lactoferrin & iron deficiency disorders).

Iron deficiency anaemia (IDA) is an important topic worldwide, with particular importance in pregnancy. 41.8% of pregnant women worldwide are affected, both in developing and developed countries. In Europe, the figure is 25.1% [1].

This has consequences for the health of both mother and child. On one hand, women’s well-being is impaired by symptoms such as fatigue, shortness of breath, palpitations, headaches and irritability, and on the other hand, there is an increased risk of illness and mortality associated with pregnancy and childbirth.

IDA increases the risk of premature childbirth, delays in foetal development, low birth weight and perinatal death [2-4].

The current therapy is mainly based on the administration of iron supplements, since food sources do not provide adequate replenishment. However, this often causes gastrointestinal side effects due to the increased formation of free radicals. In about 30% of patients, this means that they cannot take the recommended dose [5,6].

A 2017 meta-analysis sought to determine how effective lactoferrin was in the treatment of iron deficiency anaemia in pregnancy, in a direct comparison to treatment with iron supplements [7].

Lactoferrin can reversibly bind iron and is able to export iron from the tissues to the blood.  It helps to regulate systemic iron homeostasis via modulation of ferroportin and hepcidin synthesis (see also problems of iron balance).

Ferroportin is a transmembrane protein that transports divalent iron (Fe2+) from within the cell to the extracellular space. It is inhibited when hepcidin binds to it [8].

Hepcidin, a cationic peptide hormone, is the main regulator of iron homeostasis.  Iron stores, and hypoxia can modulate its production. Hepcidin degrades the ferroportin transporter, meaning that high hepcidin levels lead to reduced iron export by ferroportin.  This leads to an iron overload in the cell. During inflammation, iron export is significantly impaired, because the release of pro-inflammatory messengers results in increased expression of hepcidin [8].

Three controlled randomised studies with a total of 600 female subjects were included in this 2017 meta-analysis. Haemoglobin was the primary outcome measure, with secondary blood parameters such as serum ferritin and iron, as well as the rate of gastrointestinal adverse effects.

The administration of lactoferrin (2x100mg/d [9-11], or 250mg/d [12]) was shown to be as effective in iron deficiency anaemia, when compared with iron supplementation (using iron sulphate), and with significantly less gastrointestinal side effects. As these side effects often lead to lack of compliance, the authors strongly recommend lactoferrin for the treatment of iron deficiency anaemia (IDA) in pregnancy.

Another later study on iron deficiency anaemia, focussed in particular on the influence of lactoferrin on ferroportin and hepcidin [8].  Lactoferrin can down-regulate the inflammatory agent interleukin 6 (IL-6) and thus improve ferroportin-mediated iron export from the cells into the blood. 

This was an intervention study, and included both pregnant and non-pregnant women with various forms of anaemia, including inflammation-related anaemia. Using lactoferrin, the IL-6 levels were lower compared to iron sulphate, and the iron level was significantly increased. Lactoferrin was particularly effective in the treatment of inflammation-related anaemia by lowering IL-6 and hepcidin.

The authors saw in their results a greater beneficial effect from the lactoferrin therapy compared to the standard therapy with iron sulphate, reaffirming the results of the metanalysis.

Commercial lactoferrin products have been investigated, and characterized in terms of their heterogeneity.  These differences influence their functional properties. Differentiating between these characteristics is essential when using lactoferrin as a therapy [13].

The quality is determined by how the lactoferrin protein is prepared.  Quality is defined by various parameters: purity (in terms of lactoferrin protein content); the degree of protein denaturing, its bioactivity, as well as purification from materials that can adhere to the lactoferrin.  Also relevant is the iron binding capacity and the degree of saturation that exists after the extraction/production.

On the subject of bioavailability, studies also investigate the delivery format, where a gastric juice-resistant encapsulation is a clear advantage.  With this, the lactoferrin is released intact, at some distance from stomach acid degradation, meaning that the uptake via the receptors in the small intestine can be maximized [14].

In summary, lactoferrin, using the appropriate quality and format, can offer promising potential and a solution in the treatment of iron deficiency anaemia, especially in pregnant women. 

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2        Xiong X, Buekens P, Alexander S, Demianczuk N, Wollast E. Anemia during pregnancy and birth outcome: a meta-analysis. American journal of perinatology 2000; 17: 137–146.

3        Allen LH. Anemia and iron deficiency: effects on pregnancy outcome. The American journal of clinical nutrition 2000; 71: 1280S-4S.

4        Di Renzo GC, Spano F, Giardina I, Brillo E, Clerici G, Roura LC. Iron deficiency anemia in pregnancy. Women’s health (London, England) 2015; 11: 891–900.

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7        Abu Hashim H, Foda O, Ghayaty E. Lactoferrin or ferrous salts for iron deficiency anemia in pregnancy: A meta-analysis of randomized trials. European journal of obstetrics, gynecology, and reproductive biology 2017; 219: 45–52.

8        Lepanto MS, Rosa L, Cutone A, Conte MP, Paesano R, Valenti P. Efficacy of Lactoferrin Oral Administration in the Treatment of Anemia and Anemia of Inflammation in Pregnant and Non-pregnant Women: An Interventional Study. Frontiers in immunology 2018; 9: 2123.

9        Nappi C, Tommaselli GA, Morra I, Massaro M, Formisano C, Di CC. Efficacy and tolerability of oral bovine lactoferrin compared to ferrous sulfate in pregnant women with iron deficiency anemia: a prospective controlled randomized study. Acta obstetricia et gynecologica Scandinavica 2009; 88.

10     Paesano R, Torcia F, Berlutti F, Pacifici E, Ebano V, Moscarini M, Valenti P. Oral administration of lactoferrin increases hemoglobin and total serum iron in pregnant women. Biochemistry and cell biology = Biochimie et biologie cellulaire 2006; 84: 377–380.

11     Paesano R, Berlutti F, Pietropaoli M, Goolsbee W, Pacifici E, Valenti P. Lactoferrin efficacy versus ferrous sulfate in curing iron disorders in pregnant and non-pregnant women. International journal of immunopathology and pharmacology 2010; 23: 577–587.

12     Rezk M, Dawood R, Abo-Elnasr M, Al Halaby A, Marawan H. Lactoferrin versus ferrous sulphate for the treatment of iron deficiency anemia during pregnancy: a randomized clinical trial. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 2016; 29: 1387–1390.

13     Rosa L, Cutone A, Lepanto MS, Scotti MJ, Conte MP, Paesano R, Valenti P. Physico-chemical properties influence the functions and efficacy of commercial bovine lactoferrins. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 2018; 31: 301–312.

14     Kell DB, Heyden EL, Pretorius E. The Biology of Lactoferrin, an Iron-Binding Protein That Can Help Defend Against Viruses and Bacteria. Frontiers in immunology 2020; 11.